Stable aqueous solutions of anesthetic substances and process of preparing them



Patented Dec. 21, 1937 ITHETIO SUBSTANCES AND -'PROGESS -1 PREPARING THEM Adolf Kircher and Max Sienz, .Eragiikffortqon-the- Main, Germany, assignorsfto Winthrop Che micai Ccmp'any 1110., New York, N. Ys, a col-flora;-

tion of New York No Dravving. Application .Noveniber' .1, I934, ISe-. rialf No. 751,099., ln German November, 11,'

Our present invention relates to stable aqueous solutions of anesthetic substances and to a $1 10 ess of preparing them.

Therapplicationjof neutral or weakly alkaline,

5 but not inarkedlyy'ac'id solutions of anesthetic ;A solution of 20 gra ns oihydrochloride 6;; substances is of great importance in medicine and of para-aminobenzoyl-diethylaminoethanol, 052' dentistry in order to eliminate disagreeable bygram of the hydrochloride of 1-(3.4-dihydroxy effects, such as, for instance, irritating effects or phenyl)-2-aminopropanol-(1), 2 grams of sodium the like. chloride, 4 grams of potassium sulfate and 1 to 10 The commercial solutions of the salts of the 2 grams of urea inil lit r of re-distilled w r, esters or of the alkamine esters of amino-benzoic p epa ed W t use Of indifferent gases and acids and alkylaminobenzoic acids, for instance, filled into amp ul ows at 22" C. a DEC-Value of the hydrochloride of para-aminobenzoic acidof 6.3 and, When heated f 20 t s in a u diethylaminoethylester must be sterilized in a curren of steam i h w a pHv 1ue of 6.35.

rent of steam after having been filled into am- In contradistinction thereto a solution of the 15 poules. By this operation the ester may be parsame composition but not conta ni u ad tially saponified with formation of free paraafter the sterilization a pH-value of about 4.8. aminobenzoic acid. Th pH-value f th lu- Stable solutions of other substances having an tion may thus b r d d from nearly 6 t anesthetic action, such as of the hydrochloabout 4.8. ride of para-butylaminobenzoyl-dimethylamino- 20 It has already been tried to neutralize the acid methyl-Ethanol y b Prepared in an analogous by addition of small amounts of alkalies. This manner. entailed, however, a far-reaching saponification We claim: and was the cause of more acid being split off. 1.- Aqueous sterilized solutions having, after the Now we have found t t t pH-value of t sterilization, a pH-value of about 6 to about '7 25 solutions of anesthetic substances which are comp s urea and a a f an ester Of an amieasily saponifiable with formation of free acids nobenzeie c having an anesthetic effect. may during the sterilization and further storage qu us st ril d solut s hav n a t r t e be kept near the most favorable values of 6 to '7 Sterilization, p of ut 6 to about '7 by addition of even comparatively small amounts Comprising about 01 to about p ce t o 30 of neutral urea. The amount added is generally a a d a Sa t o an ester of an amino-benzoic about 1 gram to about 2 grams of urea per 1000 cc. acid having an anesthetic tif th solution. 3. Aqueous sterilized solutions having, after t may be presumed th t when th solutions the sterilization, a pH-value of about 6 to about '7- are heated in the current of steam the urea yields uomprising abouboto about D cent of urea, 35

only the quantity of ammonium carbonate necegan inorganic acid salt of an ester of a para-aminosary for neutralizing th acid formed by t parbenzoic acid having an anesthetic efiect and a tial saponification of the ester. vase-constrictor agent. i

As substances having an anesthetic effect there Aqueous sterilized Solutions having, a te 40 may be used, for instance, the water-soluble salts', the sterilization. a nil-value of about 6 to about 7 40 such as hydrochlorides, sulfates, nitrates or tarcomprising about t about P c trates of the compounds described in U. S. Patents urea the-hydrochloride of para-amino-benzoyl- N0S 12 554 1 550 350 1 704 0 and 1 9 diethylaminoethanol and a vase-constrictor Para-aminobenzoic acid dimethylamino-methylagent 45 butylester-hydrochloride, para-butylaminoben- Pt sterilized Solutlons havmg' after zoic acid dimethylaminoethylester-hydrochloride, the of about 6 to about 7 para aminobenzoic a Cid dibutylaminopropyb comprising at out to about 0.2 per cent of urea and the hydrochloride of para-butyl-aminobenester-sulfate and para-ammobenzoic acid-2.2- Z0 r V yl dimethylaminoethanol.

F P 6. Aqueous sterilized solutions having, after 50 ri e a particularly meniwned- There may be the sterilization, a pH-value of about 6 to about 7 adfled the water'soluble Salts of agents that comprising in 1000 cc. of water about 1 to about StllCt the blood vessels, for instance, the hydro- 2 grams of urea, 20 grams f the hydrochloride chlorides 0r bltartrates 0f 1-( -4- hy r Xyof para-aminobenzoyl-diethylaminoethanol, 0,2

he yl)-2-methylaminoethanol (levo-epineph- 55 1.2 Claims. v (cruciate) nd, i ii s q rieit e a i ie r ps nol or l- (3.4 dihydronyphenyl) -2-aminoethanol.

The following example i-llu strates the invention, I

but is not intended to limit it thereto. 7

gram of 1-(3.4-dihydroxyphenyl)rg-aminopropanol-l, 2 grams of sodium chloride and 4 grams of potassium sulfate.

7. In the process of sterilizing an aqueous solution of a salt of an ester of an amino benzoic acid having an anesthetic effect by heating said solution, the step of preventing the liberation of free acid which comprises adding urea to said solution before the heat treatment.

8. In the process of sterilizing an aqueous solution of a salt of an ester of aminobenzoic acid having an anesthetic efiect by heating said solution, the step of preventing the liberation of free acid which comprises adding aboutl to about 2 grams of urea to 1000 cc. of said solution before the heat treatment.

9. In the process of sterilizing an aqueous solution of an inorganic acid salt of an ester of para-aminobenzoic acid having an anesthetic effect and a vaso-constricting agent by heating said solution, the step of preventing the liberation of free acid which comprises adding about 1 to about 2 grams of urea to 1000 cc. of said solution before the heat treatment.

10. In the process of sterilizing an aqueous solution of the hydrochloride of para-aminobenzoyldiethylaminoethanol and a vasoconstricting agent by heating said solution, the step of preventing the liberation of free acid which comprises adding about 1 to about 2 grams of urea to 1000 cc. of said Solution before the heat treatment.

11. In the process of sterilizing an aqueous solution of the hydrochloride of para-butylaminobenzoyl-dimethylaminoethanol by heating said solution, the step of preventing the liberation of free acid which comprises adding about 1 to about 2 grams of urea to 1000 cc. of said solution before the heat treatment.

12. In the process of sterilizing an aqueous solution of 20 grams of the hydrochloride of paraaminobenzoyl-diethylamino-ethanol, 0.2 gram of 1 (3.4-dihydroxyphenyl) -2-aminopropanol-1, 2 grams of sodium chloride and 4 grams of potassium sulfate by heating said solution, the step of preventing the liberation of free acid which comprises adding about'l to about 2 grams of urea to 1000 cc. of said solution before the heat treatment.

ADOLF KIRCHER. MAX SIENZ. 

